Prescription opioid abuse and dependence are increasing public health problems in the U.S. with nearly 2 million people meeting DSM-IV criteria for a prescription opioid use disorder. While treatment demand continues to grow, only three medications are FDA-approved and a broader spectrum of treatment options is needed. A large body of evidence supports the hypothesis that cannabinoid (CB) agonists may be useful pharmacotherapies for the treatment of opioid dependence. CB agonists are already approved, available for human testing, and used for indications relevant to opioid withdrawal symptomatology. Two proof-of-concept, placebo-controlled, inpatient laboratory-based studies are proposed to evaluate the efficacy of the CB agonists, dronabinol and nabilone. Experiments 1 and 2 will employ within-subject crossover designs with the classic morphine substitution procedure whereby opioid dependent volunteers (n=10/study) are stabilized on a fixed dose of morphine (15 mg/qid). On a scheduled basis, subjects receive double-blind substitution of placebo for morphine to induce a period of spontaneous opioid withdrawal. Double-blind test doses are then administered to determine their ability to suppress opioid withdrawal signs and symptoms as the initial target for potential efficacy in treatment. Exp. 1 will examine dronabinol (5, 10, 20 and 30 mg) and Exp. 2 will examine nabilone (1, 2, 4 and 6 mg) for efficacy and safety; each of these studies includes positive (morphine 15 and 30 mg) and negative (placebo) control conditions. A broad array of physiological, subjective, observer-rated and psychomotor performance measures will be collected to assess safety, tolerability and efficacy at withdrawal suppression. These studies are innovative and significant as they are the first, to our knowledge, to examine the efficacy of CB1 agonists as potential pharmacotherapies for the treatment of opioid dependence in humans and will yield new data on the interaction of CB1 and opioid systems. Moreover, they will provide critical data to guide drug and dose selection for future studies aimed at examining their potential efficacy for use in the treatment of opioid dependence for maintenance, relapse prevention, ambulatory detoxification and/or as transitional agents for initiating opioid antagonist therapy.